Evidence suggests that brain tissues of patients with Alzheimer’s disease (AD) are easily attacked by oxidative stress, and numerous studies indicate that heme oxygenase (HO) is a major cell adaptive responder to stress. However, whether HO-1 and HO-2 play different roles in this process has not yet been studied. In the present study, it was shown in an AD model that HO-1 and HO-2 have different roles in the early stages of AD. Learning and memory ability was tested in APPswe/PS1ΔE9 (APP/PS1) transgenic and wild-type mice using the Morris water maze. β-amyloid plaques were measured using immunofluorescence staining. Changes in reactive oxygen species (ROS) levels in the hippocampi were measured using a fluorescence technique. The results indicated that the escape latency, amyloid plaque deposition and ROS production increased in the hippocampi of APP/PS1 transgenic mice compared with wild-type mice. Furthermore, using double-immunofluorescence staining and western blot analysis, it was found that the expression of HO-1 and HO-2 increased in the hippocampi of APP/PS1 mice and, notably, HO-2 was also found to be overexpressed in astrocytes. Little difference was observed in the plasma HO-1 concentrations between the two groups, while the plasma HO-2 concentration of the APP/PS1 mice was lower than that of the wild-type mice, shown by ELISA. In conclusion, HO-2 overexpression is an early event and plays a more critical role in the progression of AD.